tbuckley/cabot-search huggingface dataset:
Abstract 5523: Impact of COVID-19 on longitudinal breast cancer research studies involving TNBC patients
Authors: Cherie Bates, Esther Kong, Elena Zaikova, Samuel Aparicio, Karen Gelmon
Journal: Cancer Research (2023)

Abstract Background Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancer diagnoses but is linked to worse outcomes and comprises a disproportionate number of breast cancer deaths. The TNBC pilot study is a prospective longitudinal study to provide a critical resource for understanding TNBC disease. However, the pandemic impacted the collection of samples. Objective To highlight the impacts of COVID-19 on this longitudinal cancer translational research study including the patient's perspective and to develop recommendations to avoid future disruptions. Methods 389 participants were enrolled in the prospective longitudinal cohort, which collected serial blood samples for up to 5 years. Due to the pandemic, research was curtailed for 6 months due to concerns about patient safety, halting the collection of blood samples. Missed samples and data gaps were documented. To complement this, we initiated a survey capturing the patient perspective on their experience of the study disruption due to COVID. Results 217 enrolled participants missed a blood draw or had a collection outside the study window. 158 patients missed 1 time-point collection, and 59 patients missed ≥ 2 collections. Of the 217 participants who missed a collection, 6 disease recurrence diagnoses and 3 deaths occurred during research curtailment. The collection of survey responses from participants is ongoing and will be presented at the AACR Annual Meeting. Conclusion Missed samples resulted in irreplaceable data gaps critical to monitoring patient outcomes, and reduced cohort sampling during the pandemic. Our current knowledge of the risks suggests that with proper informed consent, collections could have continued. To mitigate disruption in future clinical studies, clear plans should be part of study design to provide continuity. The participants’ experience to be reported will also help researchers understand their issues and help develop policies. Missed collections and clinical events during COVID-19 research curtailment Number of patients Total with missed or late blood draws 217 Missed 1 collection 158 Missed ≥ 2 collections 59 Diagnosed with disease recurrence 6 Deaths 3 Citation Format: Cherie Bates, Esther Kong, Elena Zaikova, Samuel Aparicio, Karen Gelmon. Impact of COVID-19 on longitudinal breast cancer research studies involving TNBC patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5523.
Abstract 3591: Does the metastatic immunoenvironment determine poor immunotherapy responses
Authors: Nicole D. Barth, Floris J. van Dalen, Camille Duran, Utsa Karmakar, Lorena Mendive-Tapia, Takanori Kitamura, Martjin Verdoes, John S. Condeelis, Maja Oktay, Marc Vendrell, Valerie Brunton, David Entenberg
Journal: Cancer Research (2023)

Abstract Despite new treatments, cancer remains the second leading cause of death worldwide with breast cancer being the most common type. Of these deaths, the majority are due to the formation of distant metastases. While new immunotherapies have shown some success in primary tumors, their efficacy in combating metastases has been lacking. Thus we aim to investigate the hypothesis that immune responses at the metastatic site contribute to limitations of current therapies.Within the last decade, new microscopy technologies now enable real-time visualization of immune responses at primary and secondary sites. Here, we present use of these microscope technologies, along with the development of novel probes to detect apoptotic cancer cells, to investigate the success of checkpoint inhibitors in the primary and secondary sites. We validate, in multiple in vitro and in vivo assays (including intravital imaging), that fluorescent cyclic amphipathic peptide probes specifically label cells undergoing therapy-induced cancer death. In addition, we introduce a newly developed fluorescent, enzyme-activatable, chemokine-conjugate capable of targeting defined macrophage subsets in live tumors. This chemokine-conjugate exploits the high expression of chemokine receptors (e.g. CCR2) and the activity of cysteine cathepsins in tumor associated macrophages to selectively target and eradicate them without affecting other macrophages or immune cells (e.g., neutrophils, T cells, B cells). This research will help to elucidate the role of combination therapy on the metastatic foci and will provide the first insights into the benefit and limitations of combination therapy on secondary site immune responses. Citation Format: Nicole D. Barth, Floris J. van Dalen, Camille Duran, Utsa Karmakar, Lorena Mendive-Tapia, Takanori Kitamura, Martjin Verdoes, John S. Condeelis, Maja Oktay, Marc Vendrell, Valerie Brunton, David Entenberg. Does the metastatic immunoenvironment determine poor immunotherapy responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3591.
Abstract 2113: The age-dependent intratissue accumulation of cholesterol, resulting in reduced squalene epoxidase, is associated with a high colorectal cancer risk population
Authors: Soo Young Jun, Ji-Yong Yoon, Jeong-Ju Lee, Nam-Soon Kim
Journal: Cancer Research (2023)

Abstract Objective: we recently reported that cholesterol accelerates CRC aggravates via the dissociation of GSK3β/p53 by the degradation of squalene epoxidase (SQLE). However, despite its clinical reports, the underlying mechanisms between age, cholesterol, and CRC aggravation have never been evaluated in human cohorts. Design: tissue lysates and human specimens collected prospectively from CRC patients and controls were grouped according to CRC grade and divided into two groups based on age 50, the average risk for CRC. The intra-tissue content of total cholesterol and cholesteryl ester were measured using CRC lysates. We then used fluorescence-based multiplex immunohistochemistry with digital image analysis and machine learning to measure the quantitative expression of SQLE, GSK3β, p53wt, and p53mt. Results: through an epidemiological study, we estimated age-dependent increases in CRC incidence and the percentage of a group with high cholesterol around age 50. Considering this age-dependency, we demonstrated age and CRC-grade-dependent manner cholesterol accumulated inside CRC tissues, SQLE, p53wt, and p53mt degraded, and GSK3β inactivated. SQLE and GSK3β were clinically associated with increased risk and showed good diagnostic and prognostic performance in CRC patients older than 50. Furthermore, the combined value for four variables exhibited superior diagnostic performance in discriminating from CRC patients after age 50 to controls. Conclusion: this study provides new biological perceptions explaining the effects of age in the progression of CRC aggravation and potential biomarkers associated with a high CRC-risk population. Citation Format: Soo Young Jun, Ji-Yong Yoon, Jeong-Ju Lee, Nam-Soon Kim. The age-dependent intratissue accumulation of cholesterol, resulting in reduced squalene epoxidase, is associated with a high colorectal cancer risk population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2113.
Abstract 3327: Proteomic profiling of extracellular vesicles in patients with biliary tract cancers
Authors: Dong Uk Kim, Sunghee Park, Sung Yong Han, Daye Jeon, Hyeji Lee, Jonghyun Lee, Hyeong Seok Nam, Dong Wook Lee, Chang-Min Cho, Min Kyu Jung, Jun Heo, Un-Beom Kang, Seong-Jun Park, Sunghyun Huh, Yourae Shin
Journal: Cancer Research (2023)

Abstract Background and Aim: Biliary tract cancers (BTCs) have a poor prognosis. One of the reasons for the prognosis is the difficulty of early diagnosis. The absence of a sufficient biomarker to screen for BTCs in high-risk populations makes the patient to be recognized in advanced status. Therefore, it is urgent to discover a biomarker for early detection of BTCs. This study analyzed extracellular vesicle (EV) peptides to find a new serum biomarker of BTCs. Methods: Plasma samples were obtained from 5 healthy people as control, 10 from patients with benign biliary diseases such as choledocholithiasis, sclerosing cholangitis, and gallbladder polyp, and 29 from BTCS patients. The EV peptides have been obtained from 2.5ml of patient plasma. The EV peptide samples were analyzed by liquid chromatography-data-dependent acquisition-tandem mass spectrometry (LC-DDA-MS/MS). The acquired peptides and proteins were investigated by searching in Fragpipe-MSFragger. Characterization was performed using the EVs database of previous studies. After that, Differential Expression Protein (DEP) analysis and Pathway/GO analysis are performed to know the biological process. Results: Total 25,382 peptides and 3,313 proteins were defined (PSM, peptide-level FDR 1%). Most of the gene ontology biological processes were related to vesicle-mediated transport. On DEP analysis, total 72 proteins were up-regulated, and 29 proteins were down-regulated. Compared to cancer samples, 9 proteins were up-regulated to both healthy and benign samples and 2 were down-regulated. According to biological process/pathway analysis, up-regulated 9 proteins were mostly related to cytoskeleton/ECM and Hemostasis. Down-regulated 2 proteins were related to endocytosis and immunity. Conclusions: By analyzing EV peptides, a total of 11 proteins have been identified. With validation experiments, we expect to finalize biomarker candidates. Citation Format: Dong Uk Kim, Sunghee Park, Sung Yong Han, Daye Jeon, Hyeji Lee, Jonghyun Lee, Hyeong Seok Nam, Dong Wook Lee, Chang-Min Cho, Min Kyu Jung, Jun Heo, Un-Beom Kang, Seong-Jun Park, Sunghyun Huh, Yourae Shin. Proteomic profiling of extracellular vesicles in patients with biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3327.
Abstract 2680: Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer
Authors: Ailed M. Cruz-Collazo, Nilmary Grafals, Luis D. Borrero, Suranganie Dharmawardhane
Journal: Cancer Research (2023)

Abstract Metastasis represents a therapeutic challenge, especially in the case of triple negative breast cancer (TNBC), where patients often show recurrence and metastasis due to resistance to chemotherapy. The frontline therapy in TNBC is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, this strategy selects for non-dividing stem cells or more motile metastatic cells. Therefore, targeted treatment options are needed to overcome the recurrence and spreading of metastatic cells. We recently reported on MBQ-167, a Rac/Cdc42 inhibitor, which is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). Unpublished data show that in the MDA-MB-231 human TNBC model, MBQ-167 is as effective as Paclitaxel in reducing tumor growth and is more effective in metastasis prevention. Therefore, we hypothesize that MBQ-167 is a viable candidate for combined therapy with Paclitaxel and will reduce metastasis in TNBC. The purpose of this study is to test MBQ-167 in combination with Paclitaxel in the EGFR overexpressing MDA-MB-468 human TNBC cell line, which is highly malignant and also expresses the Rac1.B oncogenic splice variant. We found that MBQ-167 inhibits Rac, Rac1.B, and Cdc42 activation in this cell line. Next, we tested individual or combined MBQ-167 (50 mg/kg 5X a week) via oral administration and Paclitaxel (10 mg/kg 1X a week) via intraperitoneal administration in SCID mice bearing luciferase-tagged MDA-MB-468 tumors. Tumor growth and metastases were analyzed by chemiluminescence imaging followed by H&amp;E staining of extracted lungs at necropsy. Similar to our studies with the syngeneic 4T-1/Balb/C model, in this MDA-MB-468 model, Paclitaxel increased metastasis while single agent MBQ-167 significantly reduced metastasis. MBQ-167 in combination with Paclitaxel reduced the enhanced lung metastasis in response to Paclitaxel. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential combination therapy for TNBC. Citation Format: Ailed M. Cruz-Collazo, Nilmary Grafals, Luis D. Borrero, Suranganie Dharmawardhane. Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2680.
Abstract 2012: A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility
Authors: Ludovic Juen, Adam J. Collier, Anthony W. Tolcher, Myriam M. Ouberai
Journal: Cancer Research (2023)

Abstract Historically, increasing the drug-to-antibody ratio (DAR) in an antibody-drug conjugate (ADC) significantly raises aggregation propensity as a result of the hydrophobicity of the payload. Consequently, DARs are commonly limited to 4, forcing developers to incorporate very high potency payloads to achieve the required efficacy. This, combined with chemical instability and off-target uptake, often results in dose-limiting toxicities and narrow therapeutic indexes. In this study, we used a novel and flexible multivalent linker technology to construct two ADCs targeting HER-2 with the monoclonal antibody, trastuzumab and interchain cysteine bioconjugation. One ADC incorporated monomethyl auristatin E (MMAE) as the drug payload at average DAR 16 whilst the second incorporated the camptothecin analog, SN38, as the drug payload also at average DAR 16. The ADCs were characterized by liquid chromatography-mass spectrometry (LC-MS), size-exclusion chromatography (SEC), hydrophobic interaction chromatography (HIC) and SDS-PAGE and were then tested for efficacy in a range of HER-2 positive cell lines in vitro, and tumor growth inhibition studies using NCI-N87 cells in a mouse xenograft. Both ADCs remained &amp;gt; 95% monomeric (no aggregation) and demonstrated greater chemical stability in ex-vivo serum stability studies compared to comparator ADC constructs utilizing a clinically validated linker and the same payload release chemistry. In in vitro cell killing studies, the ADCs demonstrated target-specific cell killing with the SN38 average DAR 16 ADC achieving a disproportionate 30-fold increase in IC50 (by ADC concentration) compared to a DAR 8 comparator. Dose dependent tumor growth inhibition was observed in an HER-2 positive NCI-N87 mouse xenograft model with no change in mouse body weight, and good systemic exposure. These data demonstrate our capability, using a novel multivalent linker technology, to construct ADCs with DARs considerably greater than DAR 8 which are chemically stable, shield payloads from hydrophobic interactions (no aggregation), demonstrate good in vivo exposure profiles and which are highly efficacious in vitro and in vivo. Higher DARs will permit the incorporation of lower potency and targeted small molecule payloads into ADCs which will result in targeted cancer therapeutics with wider therapeutic indexes through the delivery of greater concentrations of payload to the tumor microenvironment and lower, payload-associated, dose-limiting toxicity. Citation Format: Ludovic Juen, Adam J. Collier, Anthony W. Tolcher, Myriam M. Ouberai. A novel antibody-drug conjugate platform enabling high drug-to-antibody ratios and greater payload flexibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2012.
Abstract 1304: Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver
Authors: Gilad Silberberg, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Art Hanson, Marianna Zipeto, Michael Ritchie
Journal: Cancer Research (2023)

Abstract The lack of knowledge around the mechanisms underlying metastatic progression is a major hurdle in achieving a durable response in the treatment of metastatic breast cancer (BC). Accordingly, effective therapies are not yet available, and the treatment of metastatic BC remains an unmet critical medical need. Circulating BC cancer cells can colonize the lungs, bone, brain, and liver generating metastatic lesions, which lead to poor outcomes. Liver metastases account for 30% of metastatic BC cases, therefore causing the greatest therapeutic challenge. The first line of therapy for BC liver metastasis is typically an invasive surgical resection, which unfortunately does not always resolve the metastatic lesion and requires further treatment. Unfortunately, there is currently no therapeutic standard of care (SOC) for BC liver metastasis, and therapy is selected based on the molecular profiling of primary tumor and metastasis biopsies. The scarcity of reliable and biologically relevant human experimental models, to provide a deep understanding of the molecular interactions underlying metastasis, is warranted. In this study, we exploit multiomic interrogation of breast cancer PDX models established from primary lesions, and metastasis of the liver, to uncover the molecular mechanisms underlying BC cells liver colonization. The results highlight global molecular differences between models derived from primary BC tumors and BC lesions collected from the liver. The analysis also reveals several genes at the DNA, RNA, and protein expression/activity level aiding in the adaptation of BC cell colonization in the liver. These novel findings provide insight into novel mechanisms of BC liver metastasis and highlight several targets suitable for future therapeutic intervention. Citation Format: Gilad Silberberg, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Art Hanson, Marianna Zipeto, Michael Ritchie. Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1304.
Abstract 3861: c-MYC mediated resistance to trametinib plus hydroxychloroquine in pancreatic cancer is overcome by CDK4/6 and lysosomal inhibition
Authors: Mark Silvis, Dilru Silva, Rohweder Riley, Sophia Schuman, Swapna Gudipaty, Amanda Truong, Jeffery Yap, Kajsa Affolter, Martin McMahon, Conan Kinsey
Journal: Cancer Research (2023)

Abstract Pharmacological inhibition of KRAS&amp;gt;RAF&amp;gt;MEK&amp;gt;ERK signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDA). Interestingly, combined inhibition of MEK1/2 (with trametinib, T) plus autophagy (with chloroquine, CQ, or hydroxychloroquine, HCQ) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDA cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ resistant PDA tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of palbociclib plus hydroxychloroquine. Citation Format: Mark Silvis, Dilru Silva, Rohweder Riley, Sophia Schuman, Swapna Gudipaty, Amanda Truong, Jeffery Yap, Kajsa Affolter, Martin McMahon, Conan Kinsey. c-MYC mediated resistance to trametinib plus hydroxychloroquine in pancreatic cancer is overcome by CDK4/6 and lysosomal inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3861.
Abstract 5671: MB201, a CD8+ T cell-selective anti-PD-L1 x IL-2 variant fusion protein, exhibits a potent anti-tumor efficacy without peripheral toxicity
Authors: Bom Park, Hyojoo Bang, Youngjun Jung, Sunjung Cho, Mi Seong Kim, Seok Chan Kang, Sungyoub Jung, Youngjin Park
Journal: Cancer Research (2023)

Abstract Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, is the first approved cancer immunotherapy. However, the clinical application of IL-2 is limited by systemic activation of unexpected immune cells, leading to severe toxicities including vascular leakage syndrome (VLS). These adverse effects were mainly caused by the activation of Treg and endothelial cells bearing IL-2 receptor (IL-2R) αβγ. Recently, studies have mainly focused on the optimization of IL-2Rs binding affinity to selectively invigorate CD8+ T cells in tumors, but the toxicity risk has yet to be solved. To overcome these limitations, we developed MB201, a novel anti-PD-L1 x IL-2v fusion protein, which selectively activates CD8+ T cells by attenuating binding affinity to IL-2Rβγ with no binding to IL-2Rα. MB201 showed a strong binding affinity to PD-L1 (KD value is 0.5 nM) and a weak binding affinity to IL-2Rβγ and IL-2Rαβγ (KD value is 23.8 nM and 30.6 nM, respectively), indicating the preferential targeting PD-L1+ tumor cells. MB201 exhibited a preferential activation of CD8+ T cells than Treg cells, which showed remarkably reduced activation compared to rhIL-2 (more than 100-fold based on EC50). Consistently with the result of T cell activation, MB201 only increased the expansion of CD8+ T cells rather than Treg cells in CD3-stimulated PBMC. Indeed, MB201 induced negligible expansion of immune cells and lower pro-inflammatory cytokine release compared to the rhIL-2 in CD3-unstimulated PBMC, indicating the reduced peripheral toxicity risk. When administered to MC38 syngeneic mice, MB201 showed superior anti-tumor efficacy without both body weight reduction and lung weight gain compared to the avelumab monotherapy or combination therapy with rhIL-2. These preclinical observations support that MB201 has characteristics of a superb safety profile and excellent anti-tumor efficacy, and it may offer an advantageous therapeutic strategy for the treatment of cancer. Citation Format: Bom Park, Hyojoo Bang, Youngjun Jung, Sunjung Cho, Mi Seong Kim, Seok Chan Kang, Sungyoub Jung, Youngjin Park. MB201, a CD8+ T cell-selective anti-PD-L1 x IL-2 variant fusion protein, exhibits a potent anti-tumor efficacy without peripheral toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5671.